Discovery and Mechanistic Elucidation of NQO1-Bioactivatable Small Molecules That Overcome Resistance to Degraders.

Degraders hold the promise to efficiently inactivate previously intractable disease-relevant targets. Unlike traditional inhibitors, degraders act substoichiometrically and rely on the hijacked proteolysis machinery, which can also act as an entry point for resistance. To fully harness the potential...

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Detalles Bibliográficos
Autores: Barbosa, Bárbara M. G., Sfyaki, Aikaterini, Rafael, Sergi, José-Duran, Ferran, Pous, Joan, Sánchez Zarzalejo, Carolina, Perez-Lopez, Carles, Vilanova, Mar, Cigler, Marko, Gay i Marín, Marina, Vilaseca Casas, Marta, Winter, Georg E., Riera i Escalé, Antoni, Mayor-Ruiz, Cristina
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2023
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/208255
Acceso en línea:https://hdl.handle.net/2445/208255
Access Level:acceso abierto
Palabra clave:Proteïnes
Cèl·lules canceroses
Proteins
Cancer cells
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spelling Discovery and Mechanistic Elucidation of NQO1-Bioactivatable Small Molecules That Overcome Resistance to Degraders.Barbosa, Bárbara M. G.Sfyaki, AikateriniRafael, SergiJosé-Duran, FerranPous, JoanSánchez Zarzalejo, CarolinaPerez-Lopez, CarlesVilanova, MarCigler, MarkoGay i Marín, MarinaVilaseca Casas, MartaWinter, Georg E.Riera i Escalé, AntoniMayor-Ruiz, CristinaProteïnesCèl·lules cancerosesProteinsCancer cellsDegraders hold the promise to efficiently inactivate previously intractable disease-relevant targets. Unlike traditional inhibitors, degraders act substoichiometrically and rely on the hijacked proteolysis machinery, which can also act as an entry point for resistance. To fully harness the potential of targeted protein degradation, it is crucial to comprehend resistance mechanisms and formulate effective strategies to overcome them. We conducted a chemical screening to identify synthetic lethal vulnerabilities of cancer cells that exhibit widespread resistance to degraders. Comparative profiling followed by tailored optimization delivered the small molecule RBS-10, which shows preferential cytotoxicity against cells pan-resistant to degraders. Multiomics deconvolution of the mechanism of action revealed that RBS-10 acts as a prodrug bioactivated by the oxidoreductase enzyme NQO1, which is highly overexpressed in our resistance models. Collectively, our work informs on NQO1 as an actionable vulnerability to overcome resistance to degraders and as a biomarker to selectively exploit bioactivatable prodrugs in cancer.Wiley-VCH2024202420232024info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion1 p.application/pdfhttps://hdl.handle.net/2445/208255Articles publicats en revistes (Química Inorgànica i Orgànica)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1002/anie.202316730Angewandte Chemie-International Edition, 2023, p. e202316730https://doi.org/10.1002/anie.202316730(c) Wiley-VCH, 2023info:eu-repo/semantics/openAccessoai:recercat.cat:2445/2082552026-05-29T05:05:01Z
dc.title.none.fl_str_mv Discovery and Mechanistic Elucidation of NQO1-Bioactivatable Small Molecules That Overcome Resistance to Degraders.
title Discovery and Mechanistic Elucidation of NQO1-Bioactivatable Small Molecules That Overcome Resistance to Degraders.
spellingShingle Discovery and Mechanistic Elucidation of NQO1-Bioactivatable Small Molecules That Overcome Resistance to Degraders.
Barbosa, Bárbara M. G.
Proteïnes
Cèl·lules canceroses
Proteins
Cancer cells
title_short Discovery and Mechanistic Elucidation of NQO1-Bioactivatable Small Molecules That Overcome Resistance to Degraders.
title_full Discovery and Mechanistic Elucidation of NQO1-Bioactivatable Small Molecules That Overcome Resistance to Degraders.
title_fullStr Discovery and Mechanistic Elucidation of NQO1-Bioactivatable Small Molecules That Overcome Resistance to Degraders.
title_full_unstemmed Discovery and Mechanistic Elucidation of NQO1-Bioactivatable Small Molecules That Overcome Resistance to Degraders.
title_sort Discovery and Mechanistic Elucidation of NQO1-Bioactivatable Small Molecules That Overcome Resistance to Degraders.
dc.creator.none.fl_str_mv Barbosa, Bárbara M. G.
Sfyaki, Aikaterini
Rafael, Sergi
José-Duran, Ferran
Pous, Joan
Sánchez Zarzalejo, Carolina
Perez-Lopez, Carles
Vilanova, Mar
Cigler, Marko
Gay i Marín, Marina
Vilaseca Casas, Marta
Winter, Georg E.
Riera i Escalé, Antoni
Mayor-Ruiz, Cristina
author Barbosa, Bárbara M. G.
author_facet Barbosa, Bárbara M. G.
Sfyaki, Aikaterini
Rafael, Sergi
José-Duran, Ferran
Pous, Joan
Sánchez Zarzalejo, Carolina
Perez-Lopez, Carles
Vilanova, Mar
Cigler, Marko
Gay i Marín, Marina
Vilaseca Casas, Marta
Winter, Georg E.
Riera i Escalé, Antoni
Mayor-Ruiz, Cristina
author_role author
author2 Sfyaki, Aikaterini
Rafael, Sergi
José-Duran, Ferran
Pous, Joan
Sánchez Zarzalejo, Carolina
Perez-Lopez, Carles
Vilanova, Mar
Cigler, Marko
Gay i Marín, Marina
Vilaseca Casas, Marta
Winter, Georg E.
Riera i Escalé, Antoni
Mayor-Ruiz, Cristina
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Proteïnes
Cèl·lules canceroses
Proteins
Cancer cells
topic Proteïnes
Cèl·lules canceroses
Proteins
Cancer cells
description Degraders hold the promise to efficiently inactivate previously intractable disease-relevant targets. Unlike traditional inhibitors, degraders act substoichiometrically and rely on the hijacked proteolysis machinery, which can also act as an entry point for resistance. To fully harness the potential of targeted protein degradation, it is crucial to comprehend resistance mechanisms and formulate effective strategies to overcome them. We conducted a chemical screening to identify synthetic lethal vulnerabilities of cancer cells that exhibit widespread resistance to degraders. Comparative profiling followed by tailored optimization delivered the small molecule RBS-10, which shows preferential cytotoxicity against cells pan-resistant to degraders. Multiomics deconvolution of the mechanism of action revealed that RBS-10 acts as a prodrug bioactivated by the oxidoreductase enzyme NQO1, which is highly overexpressed in our resistance models. Collectively, our work informs on NQO1 as an actionable vulnerability to overcome resistance to degraders and as a biomarker to selectively exploit bioactivatable prodrugs in cancer.
publishDate 2023
dc.date.none.fl_str_mv 2023
2024
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/208255
url https://hdl.handle.net/2445/208255
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1002/anie.202316730
Angewandte Chemie-International Edition, 2023, p. e202316730
https://doi.org/10.1002/anie.202316730
dc.rights.none.fl_str_mv (c) Wiley-VCH, 2023
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Wiley-VCH, 2023
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 1 p.
application/pdf
dc.publisher.none.fl_str_mv Wiley-VCH
publisher.none.fl_str_mv Wiley-VCH
dc.source.none.fl_str_mv Articles publicats en revistes (Química Inorgànica i Orgànica)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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